Research Paper Volume 12, Issue 24 pp 25744—25766
Alisol B 23-acetate activates ABCG5/G8 in the jejunum via the LXRα/ACAT2 pathway to relieve atherosclerosis in ovariectomized ApoE-/- mice
- 1 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- 2 National Standard Laboratory of Pharmacology of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
- 3 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
- 4 Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
- 5 Institute of Pediatrics, Jiangsu Key Laboratory of Pediatric Respiratory Disease, Nanjing University of Chinese Medicine, Nanjing 210023, China
- 6 Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing 210023, China
Received: April 27, 2020 Accepted: October 6, 2020 Published: November 25, 2020
https://doi.org/10.18632/aging.104185How to Cite
Abstract
Phytosterols have been shown to improve blood lipid levels and treat atherosclerosis. This research investigated the effects of phytosterol Alisol B 23-acetate (AB23A) on jejunum lipid metabolism and atherosclerosis. The results show that intragastric administration of AB23A can significantly reduce atherosclerotic plaque area and lipid accumulation in the jejunum of ovariectomized ApoE-/- mice fed a high-fat diet and can also improve the lipid mass spectra of the plasma and jejunum. In vitro studies have shown that AB23A can increase cholesterol outflow in Caco-2 cells exposed to high fat concentrations and increase the expression of ATP-binding cassette transfer proteins G5/G8 (ABCG5/G8), the liver X receptor α (LXRα). Furthermore, inhibition of LXRα can significantly eliminate the active effect of AB23A on decreasing intracellular lipid accumulation. We also confirmed that AB23A has a negative effect on Acyl-CoA cholesterol acyltransferase 2 (ACAT2) in Caco-2 cells cultured in the high concentrations of fat, and we found that AB23A further reduces ACAT2 expression in cells treated with the ACAT2 inhibitor pyripyropene or transfected with ACAT2 siRNA. In conclusion, we confirmed that AB23A can reduce the absorption of dietary lipids in the jejunum by affecting the LXRα-ACAT2-ABCG5/G8 pathway and ultimately exert an anti-atherosclerotic effect.
Abbreviations
AS: atherosclerosis; TC: total cholesterol; TG: total triglycerides; LDL-c: low density lipoprotein cholesterol; HDL-c:high density lipoprotein cholesterol;CM: chylomicrons; preβ1-HDL: preβ1 High density lipoprotein; ABCG5: ATP binding cassette transporter G5; ABCG8: ATP binding cassette transporter: G8; ABCA1: ATP binding cassette transporter A1; LXRα: liver X receptor α; LXRβ: liver X receptor β; FXR: Farnesol X receptor; ACAT2: Acyl-CoA-cholesteryl acyltransferase 2; HMGCR: hydroxymethylglutarate monoacyl-CoA reductase; ACC: acetyl-CoA carboxylase; ACS: acyl-CoA synthesis Enzymes; SREBP: Sterol regulatory element binding protein; MTP: Microsomal triglyceride transfer protein; CYP7A1: cholesterol 7-alpha hydroxy-lase; RCT: Reverse cholesterol transport; OVX: Ovariectomy; AB23A: Alisol B 23-acetate; HFD: high-fat diet; HPLC-Q-TOF/MS: High performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry; FC: free cholesterol; CE: cholesterol ester; TAG: triglyceride; DAG: diglyceride; FA: free fatty acid; PC: phosphatidylcholine; PE: phosphatidy lethanolamine; PI: phosphatidylinositol; TBA: total bile acid; ALT: alanine transaminase; AST: aspartate transaminase; PBS: phosphate buffered saline; OCT: optimal cutting temperature compound; FBS: fetal bovine serum; BSA: bovine serum albumin; PBS: phosphate buffer saline; MTT: 3-(4:5-dimethylthiazol-2-yl)-2:5-diphenyltetrazolium bromide; PMSF: benzene methylsulfonyl fluoride; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; PVDF: polyvinylidene fluoride film; TBS-T: Tween-20 Tris buffered saline; ECL: enhanced chemiluminescence.